Transcript Chronic leukemias

Chronic leukemias
Chronic leukemias

Chronic myelogenous (granulocytic) leukemia


Is characterized by an unregulated proliferation of
myeloid elements in the bone marrow, liver and
spleen, leading to marked leukocytosis and
organomegaly.
Incidence



20% of all leukemias
Primarily affects adults 25-60 years old, with a peak
incidence at 40-59.
Etiology, pathogenesis and physiology

May occur after anything that can induce chromosomal
aberrations such as ionizing radiation, alkylating agents,
and exposure to other biologically active chemicals
Chronic leukemias

Appears to be a clonal hematopoietic stem cell disorder




90% of CML have a Philadelphia (Ph’) chromosome
(reciprocal translocation between chromosome 22 and
chromosome 9) by cytogenetic karyotype studies. A
BCR/ABL hybrid gene is created. The gene product has
enhanced tyrosine kinase activity that results in
 Increased granulocyte-colony stimulating factor
 Increased platlet derived growth factor
 Suppression of apoptosis in hematopoietic cells
The remaining 5-10% are positive for the translocation
using more sensitive DNA studies such as RT-PCR or
fluorescent in situ hybridization
The Ph’ chromosome is found in all hematopoietic cells
except T lymphocytes (and sometimes B lymphocytes)
The Ph’ cells have a growth advantage over normal cells
Philadelphia chromosome
Chronic leukemias




The progeny of the original malignant cell, after 2-6 years,
eventually replace the normal hematopoietic elements and
become the prominent cell
By the time the disease becomes clinically evident, nearly
all the myeloid cells in the bone marrow are Ph’ +
As the disease progresses, the Ph’ + cells undergo
additional chromosomal aberrations and the patients
ultimately terminate in a blast crisis.
The clinical course of the disease occurs in three stages


Asymptomatic, proliferative stage – Ph’+ cells appear in
the bone marrow and the peripheral leukocyte count is
normal
The symptomatic, chronic stage occurs after about 6.3
years – at this stage the peripheral leukocyte count is
increased and immature granulocytes appear in the
peripheral blood.
Chronic leukemias
The hyperproliferation is easily controlled with
chemotherapy, but the remission is only temporary
and patients still have Ph’+ cells in the bone marrow.
Accelerated or acute stage – this is also called a blast crisis
(>30% blasts in the bone marrow)
 Cellular proliferation is uncontrollable and resembles
AML.
 The medium survival is 10 weeks



Signs and symptoms






Malaise
Fatigue due to anemia
Fever
Weight loss
Sweating
Bone aches and fullness in upper abdomen due to
expansion of the bone marrow and organomegaly
Chronic leukemias


Bleeding, petechiae, ecchymoses from abnormal
platlets
Lab features




Leukocytosis and anemia; ¾ have WBC counts> 100
x 109/L
Normal appearing granulocytes at all stages of
maturation are seen in the peripheral smear (they
are not functionally normal, however); < 10% are
blasts and promyelocytes
Many have a thrombocytosis with variation in shape;
platlet function is frequently abnormal
Low to absent leukocyte alkaline phosphatase
activity (Low LAP score)
CML
CML – abnormal platlet
CML – blast transformation
Chronic leukemias

Treatment





Median survival from the time of diagnosis used to be ~ 3
years
The prognosis is better if the WBC count is lower and the
% of blasts is low
Chemotherapy with a single agent has been used and ~
75% in the chronic phase of the disease go into remission.
However, Ph’+ cells remain in the bone marrow
Bone marrow transplants during the chronic phase (high
dose chemo/radiotherapy followed by infusion of normal,
compatible bone marrow) used to be the best therapy
A new drug, Gleevec, is now available and it specifically
targets the BCR/ABL gene product. The Ph’ + cells are
destroyed, while normal cells are unaffected
Chronic leukemias

Eosinophilic leukemia




Is this a distinct entity or a variant of CML?
30-70% eosinophils with a WBC count > 30 x
109/L and a shift to the left
The prognosis is poor with a median survival of <
1 year
Basophilic leukemia

Is this a distinct entity or a variant of CML?

Is extremely rare with 40-80% basophils and a left shift
Chronic leukemias

Chronic lymphocytic leukemia




This is predominantly a disease of the elderly; >
90% are over 50 and 2/3 are over 60;
male:female is 2:1
Is characterized by peripheral and bone marrow
lymphocytosis and a survival of a few years to >
10 years
This is a B cell abnormality
The lymphocytes appear normal, but are
immunologically incompetent. However, some
functionally normal B cells remain and there is a
normal T cell pool
Chronic leukemias

Etiology


Clinical course




Genetic factors are important since it runs in families
The pace of the disease varies and is dependent on the
rate of accumulation of abnormal lymphocytes
Median survival is 3-4 years, but 10-15% survive >
10years
There is no tendency for blast transformation, but
complications of advanced disease result from
progressive accumulation of long-lived, poorly functional
lymphocytes.
Signs and symptoms


Organomegaly and lymphadenopathy
Often discovered accidentally
Chronic leukemias


Near the end – bruising, pallor, fever, and weight loss
Lab features





Absolute lymphocytosis of 10-150 x 109/L
Lymphocytes usually appear normal, but they are
markedly fragile and smudge cells are seen on the
peripheral smear
It is not necessary to do a bone marrow biopsy for
diagnosis.
Anemia occurs late in the disease and may be due to
decreased production secondary to marrow infiltration,
hypersplenism, or autoimmune hemolytic anemia: the
same things may cause neutropenia or
thrombocytopenia
Hypogammaglobulinemia as the disease progresses
CLL with smudge cells
Chronic leukemias

Prognosis is related to the extent and
distribution of the disease – also called the
stage:



Stage A – lymphocytosis without anemia or
thrombocytopenia and < 3 areas of lymphoid
involvement (lymph nodes, spleen, liver)
Stage B – same as A, but > 3 areas of
lymphoid involvement
Stage C – lymphocytosis with anemia,
thrombocytopenia, or both
Chronic leukemias

Treatment





Stage A – observe only
Stage B with no symptoms – same as A
Stage B with symptoms - therapeutic
intervention to relieve signs and symptoms
Stage C - therapeutic intervention to relieve
signs and symptoms
The goal of therapy is simply to relieve signs
and symptoms
Chronic leukemias

Differential diagnosis

Must distinguish between CLL and prolymphocytic
leukemia, hairy cell leukemia, large, granular
lymphocyte leukemia, Sezary’s syndrome, and
circulating lymphoma cells

Prolymphocyte leukemia


This is an aggressive leukemic disorder of mature B or T
cells
> 55% of the lymphocytes are prolymphocytes which are
large with moderate amounts of pale basophilic cytoplasm,
mature condensed chromatin, and a single prominent
nucleolus
Prolymphocytic leukemia
Chronic leukemias

Hairy cell leukemia







This is mainly a disease of elderly men
Patients present with marked splenomegaly, but not
lymphadenopathy
Patients have fatigue and malaise
Pancytopenia
The peripheral smear shows atypical mononuclear
lymphocytoid cells with hairy projections on their surfaces
The bone marrow yields a dry tap because the malignant
cells are often surrounded by fibrosis
Splenectomy and interferon as well as new
chemotherapeutic drugs are successful in promoting long
lasting remissions
Hairy cell leukemia
Chronic leukemias

Large, granular lymphocyte leukemia





T cell or NK cell in origin
Is characterized by a moderate lymphocytosis composed of
cells with abundant pale-staining cytoplasm and nuclei
with mature, clumped chromatin
Anemia is common, but neutropenia is rare
Most patients survive > 10 years
Sezary’s syndrome


Occurs in patients with cutaneous T cell lymphoma
The lymphocytes seen in the peripheral smear have a very
large, convoluted nuclear outline and finely distributed
chromatin
Large, granular lymphocyte
leukemia
Sezary’s syndrome
Chronic leukemias

Circulating lymphoma cells

Patients with non-Hodgkins lymphoma may develop
peripheral blood involvement